ASCO Breast Cancer Updates - Living Beyond Breast Cancer · Progress in all Receptor Subtypes! ......
Transcript of ASCO Breast Cancer Updates - Living Beyond Breast Cancer · Progress in all Receptor Subtypes! ......
ASCO Breast Cancer Updates
Debu Tripathy, MD
Department of Breast Medical Oncology
The University of Texas MD Anderson Cancer Center, Houston, TX
Disclosures:
Research Support: Novartis, Pfizer, Polyphor
Honoraria for Steering Committee Service: GSK, Novartis, Pfizer
Consulting: Genomic Health
Progress in all Receptor Subtypes! – HR+, Triple Negative, HER+
• Improved Survival From CDK 4/6 Inhibitor Ribociclib
• Longer Time To Progression With AKT Inhibitor
• More Precise Decision-making For Adjuvant Chemotherapy
• Improved Survival From Immunotherapy – Checkpoint Inhibitor Atezolizumab
• Engineered HER2 Antibody Provides a Benefit Over Trastuzumab (Herceptin)
• Neratinib as a HER2 Kinase Inhibitor Partner With Capecitabine
• Longer Adjuvant Endocrine Therapy – When Does It Help?
Santarpia L et al. The Oncologist 2016
The Fluid State of the Tumor Micro-Ecosystem: Genomic Evolution and
Adaptive Resistance
MONALEESA-7 Study Design
Stratification Factors • Liver/lung metastasis (yes/no)• Prior chemotherapy (yes/no)• Combination partner (NSAI/TAM)
4
Primary endpoint • PFS (local)
Key secondary endpoint • OS
Select secondary endpoints • HRQOL• ORR• TTDD of ECOG PS• Safety
Pre/perimenopausal womena with
HR+/HER2− ABC
No prior ET for ABCb
≤ 1 prior CT for ABC
N = 672
Ribociclib 600 mg/day;
3 weeks on/1 week off +
NSAI/TAMc + GOSd
n = 335
Placebo 3 weeks on/1 week off
+ NSAI/TAMc + GOSd
n = 337
ANA, anastrozole; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; FSH, follicle-stimulating hormone; GOS, goserelin; HRQOL, health-related quality of life; NSAI, nonsteroidal aromatase inhibitor; ORR, objective response rate; TAM, tamoxifen; TTDD, time to definitive deterioration. a Premenopausal status was defined as either patient had last menstrual period ≤ 12 months or if receiving TAM or toremifene for ≤ 14 days, plasma estradiol and FSH must be in normal premenopausal range or in the case of induced amenorrhea, plasma estradiol and FSH must be in normal premenopausal range. Perimenopausal status was defined as neither premenopausal nor postmenopausal (prior bilateral oophorectomy, age ≥ 60 years, or FSH and plasma estradiol levels in normal postmenopausal range). Patients could not be ≥ 60 years of age. b Patients who received ≤ 14 days of NSAI/TAM ± GOS were allowed. c TAM and NSAI were administered daily orally. TAM dose was 20 mg, LET dose was 2.5 mg. and ANA dose was 1 mg. d GOS 3.6 mg was administered by subcutaneous injection.
First Phase III trial with a CDK4/6 inhibitor exclusively in premenopausal patients
Dr Sara Hurvitz
Ran
dom
ized
1:1
CDK4/6 Controls Cell Cycle Progression From G1 to S Phase by Regulating the Activity of Rb
E2F activates transcription of genes necessary for S-phase entry and
cell cycle progression2
Synthesis of D-type cyclins (cyclin D1, D2, and D3) and association with
CDK4/6 is initiated in response to mitogenic
signaling pathways1
Active cyclin D–CDK4/6 phosphorylates Rb, decoupling Rb from E2F and allowing
transcription of genes required for cell cycle progression1
Rb inhibits E2F-mediated transcription by binding to and
sequestering E2F2
1. Lange CA, et al. Endocr Relat Cancer. 2011 2. Rader J, et al. Clin Cancer Res 2013
Figure adapted from Lange CA, et al. Endocr Relat Cancer 2011
MONALEESA-7: Primary endpoint: PFS (investigator-assessed)
Pro
bab
ility
of
PFS
(%
)
Time (months) No. at risk Ribociclib + tamoxifen/NSAI 335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0
Placebo + tamoxifen/NSAI 337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0
PFS (investigator assessment)
Ribociclib + tamoxifen/NSAI n=335
Placebo + tamoxifen/NSAI n=337
Number of events, n (%) 131 (39.1) 187 (55.5)
Median PFS, months (95% CI)
23.8 (19.2–NR)
13.0 (11.0–16.4)
10 8 6 4 2 0
100
80
60
40
20
0
30 28 26 24 22 20 18 16 14 12
10
30
50
70
90
Hazard ratio (95% CI) 0.553 (0.441–0.694)
One-sided p value < 0.0001
Tripathy D, et al. Lancet Oncol 2018
Overall Survival
7 Dr Sara Hurvitz
Ribociclib + ET Placebo + ET Events/N 83/335 109/337
Median OS, mo Not reached 40.9
HR (95% CI) 0.712 (0.535-0.948) P value .00973
Kaplan-Meier Estimate Ribociclib + ET Placebo + ET
36 months 71.9% 64.9%
42 months 70.2% 46.0%
• ≈ 29% relative reduction in risk of death
• The P value of .00973 crossed the prespecified boundary to claim superior efficacy
Landmark Analysis
Overall Survival in the NSAI Subgroup
8 Dr Sara Hurvitz
Ribociclib + ET Placebo + ET Events/n 61/248 80/247
Median OS, mo Not reached 40.7
HR (95% CI) 0.699 (0.501-0.976)
Kaplan-Meier Estimate Ribociclib + ET Placebo + ET
36 months 72.2% 64.6%
42 months 69.7% 43.0%
Landmark Analysis
• ≈ 30% relative reduction in risk of death
Time to First Subsequent Chemotherapy
9 Dr Sara Hurvitz
Ribociclib + ET Placebo + ET
Events/n 95/335 139/337
Median time to CT, months Not reached 36.9
HR (95% CI) 0.596 (0.459-0.774)
Kaplan-Meier Estimate
Ribociclib + ET Placebo + ET
36 months 67.2% 53.8%
42 months 65.8% 49.0%
Landmark Analysis
Progression-Free Survival 2
10 Dr Sara Hurvitz
Ribociclib + ET Placebo + ET
Events/n 126/335 161/337
Median PFS2, mo Not reached 32.3
HR (95% CI) 0.692 (0.548-0.875)
Kaplan-Meier Estimate
Ribociclib + ET Placebo + ET
36 months 58.4% 46.2%
42 months 54.6% 37.8%
PFS 2: time from randomization to
progression on the next line of therapy or
death
Landmark Analysis
San Antonio Breast Cancer Symposium, December 5–9, 2017
This presentation is the intellectual property of Debu Tripathy.
Contact [email protected] for permission to reprint and/or distribute.
Hematologic adverse events Regardless of study treatment relationship
AEs ≥5% in either arm, %
Ribociclib + tamoxifen/NSAI
n=335
Placebo + tamoxifen/NSAI
n=337
All Grade 3 Grade 4 All Grade 3 Grade 4
Neutropenia 75.8 50.7 9.9 7.7 3.0 0.6
Leukopenia 31.3 13.1 1.2 5.6 1.2 0
Anemia 20.9 3.0 0 10.1 2.1 0
Thrombocytopenia 8.7 0.6 0.3 2.1 0.3 0.3
• Febrile neutropenia occurred in 2.1% of patients in the ribociclib arm vs 0.6% of patients in the placebo arm
Tripathy D, et al. SABCS 2017
San Antonio Breast Cancer Symposium, December 5–9, 2017
This presentation is the intellectual property of Debu Tripathy.
Contact [email protected] for permission to reprint and/or distribute.
Non-hematologic adverse events Regardless of study treatment relationship
AEs ≥20% in either arm, %
Ribociclib + tamoxifen/NSAI
n=335
Placebo + tamoxifen/NSAI
n=337
All Grade 3 Grade 4 All Grade 3 Grade 4
Hot flush 34.0 0.3 0 33.5 0 0
Nausea 31.6 0.6 0 19.6 0.3 0
Arthralgia 29.9 0.9 0 27.3 0.9 0
Fatigue 23.6 1.2 0 24.6 0 0
Headache 23.0 0 0 24.3 0.9 0
Diarrhea 20.3 1.5 0 18.7 0.3 0
• Post-baseline QTcF >480 msec, based on ECG data, occurred in 23 patients (6.9%) in the ribociclib arm vs 4 patients (1.2%) in
the placebo arm
– Post-baseline QTcF >500 msec occurred in 5 patients (1.5%) vs 1 patient (0.3%)
• Treatment discontinuation due to QT prolongation AEs occurred in 1 patient (0.3%) in the ribociclib arm vs 2 patients (0.6%)
in the placebo arm
• QT prolongation events were not associated with clinical symptoms or arrhythmia
Tripathy D, et al. SABCS 2017
San Antonio Breast Cancer Symposium®, December 4-8, 2018
The Importance of the PI3K/AKT/mTOR Pathway in HR+ Breast Cancer
• The PI3K pathway is frequently altered in HR+
breast cancer and has been implicated in
resistance to endocrine therapies1,2
• Approximately 40% of HR+ breast cancers
harbor a PIK3CA mutation, leading to
hyperactivation of the PI3K pathway3-5
• PI3K signaling has been shown to promote
estrogen-independent growth of ER+ breast
cancer cells,6,7 and this growth is inhibited by
the addition of PI3K inhibitors to antiestrogens8 Figure reprinted by permission from Springer Nature: Nature Reviews Drug Discovery. Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery.
Hennessy BT, et al. Nat Rev Drug Discov. 2005 Dec;4(12):988-1004. © 2005.
San Antonio Breast Cancer Symposium®, December 4-8, 2018
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PI3K/AKT/PTEN pathway in ER positive Breast Cancer
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Capivasertib (AZD5363) in ER positive breast cancer
San Antonio Breast Cancer Symposium®, December 4-8, 2018
FAKTION Trial design
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Progression Free Survival in the ITT population<br />
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Progression Free Survival by PI3K/AKT/PTEN pathway activation status
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Objective Response Rates in those with measurable disease
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Overall survival
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Notable adverse events affecting >10% of the study population
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Conclusions
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Slide 1
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Background: Rationale for Integrating Genomic and Clinical Risk in Early Breast Cancer
San Antonio Breast Cancer Symposium®, December 4-8, 2018
TAILORx Results: Association between Continuous RS 11-25 and 9-Year Distant Recurrence Rate by Treatment Arms Stratified by Age (</=50 vs.>50 Years)<br />
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Objectives and Methods: TAILORx Secondary Objective
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Results: Impact of Clinical Risk (CR) on Prognosis by RS Group and Age
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Results: Absolute Differences in 9-year Distant Recurrence Rate by Clinical Risk Stratified by Age, RS, and Chemotherapy Use
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Slide 9
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Conclusions: Integrating Clinical and Genomic Risk in Breast Cancer to Guide Adjuvant Therapy
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Potential Clinical Utility of Integrated RS and Clinical Risk for Guiding Treatment in Women < 50 Years
San Antonio Breast Cancer Symposium®, December 4-8, 2018
IMpassion130: updated OS from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab + nab-paclitaxel in previously untreated locally advanced or metastatic TNBC
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Background
San Antonio Breast Cancer Symposium®, December 4-8, 2018
IMpassion130 Study Design
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Primary PFS Analysis in the ITT and PD-L1 IC+ Subgroup
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OS in ITT Population
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OS in PD-L1+ Population
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Updated Safety Analysisa
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Conclusions
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Slide 1
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Persistent Unmet Need in HER2+ MBC After Anti-HER2 Therapy
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Margetuximab: Fc-engineered to Activate Immune Responses
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Study CP-MGAH22-04 (SOPHIA) Design1,2
San Antonio Breast Cancer Symposium®, December 4-8, 2018
PFS Analysis in ITT Population
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Planned Exploratory PFS Analysis by CD16A Genotype, by CBA
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Conclusions
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Neratinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase 3 NALA trial
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Neratinib: An irreversible pan-HER TKI
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Clinical experience with neratinib
San Antonio Breast Cancer Symposium®, December 4-8, 2018
NALA study design
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Centrally confirmed PFS (co-primary endpoint)
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Prespecified restricted means analysis – PFS
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OS (co-primary endpoint)
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Time to intervention for CNS metastases
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Response rate and duration of response
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Most frequent grade 3/4 adverse events
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Conclusions
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Benefit from letrozole as extended adjuvant therapy after sequential endocrine therapy: A randomized, phase III study of the Gruppo Italiano Mammella (GIM)
San Antonio Breast Cancer Symposium®, December 4-8, 2018
GIM4 Study Design
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Treatment compliance
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Slide 9
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DFS first events by treatment
Presented By Lucia Del Mastro at 2019 ASCO Annual Meeting
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Slide 14
San Antonio Breast Cancer Symposium®, December 4-8, 2018
Extended adjuvant AI studies
Presented By Lucia Del Mastro at 2019 ASCO Annual Meeting